Identification of
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
13 10 2022
13 10 2022
Historique:
pubmed:
21
9
2022
medline:
15
10
2022
entrez:
20
9
2022
Statut:
ppublish
Résumé
DNA polymerase theta (Polθ) is an attractive synthetic lethal target for drug discovery, predicted to be efficacious against breast and ovarian cancers harboring BRCA-mutant alleles. Here, we describe our hit-to-lead efforts in search of a selective inhibitor of human Polθ (encoded by POLQ). A high-throughput screening campaign of 350,000 compounds identified an 11 micromolar hit, giving rise to the N2-substituted fused pyrazolo series, which was validated by biophysical methods. Structure-based drug design efforts along with optimization of cellular potency and ADME ultimately led to the identification of
Identifiants
pubmed: 36126059
doi: 10.1021/acs.jmedchem.2c00998
pmc: PMC9942948
mid: NIHMS1859508
doi:
Substances chimiques
DNA-Directed DNA Polymerase
EC 2.7.7.7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
13198-13215Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM124165
Pays : United States
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